Azacycloalkane derivatives, preparation and therapeutic application

ABSTRACT

The invention relates to azacycloalkane derivatives, to pharmaceutical compositions containing them, to processes for preparing them, and to methods for the treatment of hyperglycaemia, diabetes, obesity or inflammation utilizing them.

This application is a 371 of PCT/FR99/00851 filed Apr. 13, 1999.

The subject of the present invention is azacycloalkane derivatives,their preparation and their therapeutic application, especially in thetreatment of diabetes, obesity, hyperglycaemia and inflammation.

The azacycloalkane derivatives of the invention correspond to thegeneral formula (I)

in which:

R₁ represents a hydrogen atom, hydroxyl, a C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₄₋₇ cycloalkyl or C₁₋₄ alkyloxy(C₁₋₄ alkyl) group, anaminocarbonyl group, a benzyl, a heterocycloalkyl or heteroaryl groupcomprising from 4 to 5 carbon atoms and a heteroatom, such as nitrogen,sulphur or oxygen, the heterocycloalkyl or heteroaryl group beingoptionally substituted with one or two substituents such as a hydroxyl,a C₁₋₄ alkyl group or a halogen;

R₂, R₃ and R₄, which may be identical or different, representindependently of each other a hydrogen atom, a C₁₋₄ alkyl group, a C₄₋₇cycloalkyl group, a hydroxyl group, an aminocarbonyl group or aheteroaryl group comprising from 4 to 5 carbon atoms and a heteroatomsuch as nitrogen, sulphur or oxygen, the heteroaryl group beingoptionally substituted with one or two substituents such as a hydroxylgroup, a C₁₋₄ alkyl group or a halogen;

or R₁ and R₂ together form a C₃₋₆ alkylene group, a C₂₋₃ alkylenedioxygroup, a C₂₋₃ alkylenedithio group, —(O₂)S—C₂₋₃ alkylene-S(O₂)— or agroup —CH₂NHC(O)CH₂—;

or R₂ and R₃ together form a propylene or butylene group, a C₁₋₃alkylenedioxy group, a carbonyldioxy group or a 2-butenylene;

or R₂ and R₃ together form with the atoms carrying them a norbornane ora 5-norbornene or a bond in order to give a double bond between theatoms carrying them, X being a carbon atom;

R₅ represents a hydrogen atom, a hydroxyl group or, when

R₆ represents a hydrogen, a 1-indanyl group;

R₆ represents an aromatic group chosen from the following groups:

or, when R₂ and R₃ together form a C₁₋₃ alkylenedioxy or carbonyldioxygroup, a benzyl optionally substituted with one or two substituents suchas a halogen or a C₁₋₄ alkyl group, or R₆ represents a hydrogen, when R₅represents a 1-indanyl group;

R₇ represents a hydrogen atom or a C₁₋₄ alkyl group;

R₈ represents a hydrogen, an acetyl, a benzoyl, a C₁₋₄ alkyl group,optionally substituted with a hydroxyl; or

a C₁₋₂ alkylphenyl group, optionally substituted on the alkyl group witha hydroxyl,

X represents a carbon, nitrogen, oxygen or sulphur atom or a sulphonylgroup,

Y represents an oxygen or sulphur atom,

n is equal to 1 or 2; l is equal to 1 and m is equal to 0 when Xrepresents a nitrogen atom; l and m are equal to 0 when X represents asulphur or oxygen atom or a sulphonyl; they are equal to 1 when Xrepresents a carbon atom.

Within the framework of the present invention:

C_(x-y) is understood to mean a carbon chain which may have from x to ycarbon atoms;

alkyl is understood to mean a linear or branched saturated aliphaticgroup; for example, a C₁₋₄ alkyl group represents a linear or branchedcarbon chain of 1 to 4 carbon atoms, more particularly a methyl, ethyl,propyl, isopropyl, butyl, isobutyl and tert-butyl radical, the termC_(x-y) alkylene denoting a divalent C_(x-y) alkyl group;

C_(x-y) alkenyl is understood to mean a linear or branched aliphaticgroup comprising from x to y carbon atoms and 1 or 2 ethylenicunsaturations, the term C_(x-y) alkenylene denoting a divalent C_(x-y)alkenyl group;

cyclo(C_(x-y) alkyl) is understood to mean a cyclic radical comprising xto y carbon atoms;

alkoxy is understood to mean an alkyloxy group containing a linear orbranched saturated aliphatic chain;

halogen atom is understood to mean a fluorine, a chlorine, a bromine oran iodine;

heteroaryl is understood to mean a pyrrolyl, pyridyl, thyenyl, furyl orpyranyl group, preferably a pyrrolyl group; and

heterocycloalkyl is understood to mean a pyrrolidinyl, piperidyl,tetrahydrofuranyl and tetrahydropyranyl group, preferably atetrahydrofuranyl group.

The compounds of formula (I) can form with pharmaceutically acceptableacids and bases salts which form part of the invention. In particular,the compounds for which R₇ is a hydrogen can form salts with bases. Thepreferred salts of bases are, in this case, the salts of sodium and ofcalcium, which are such that R₇ represents a sodium or calcium atom.

The compounds of formula (I) possess one or more asymmetric carbonatoms; they may exist in the form of enantiomers, diastereoisomers or ofmixtures of these various forms, including racemic mixtures which formpart of the invention.

The preferred compounds according to the invention are those for which:

R₂, R₃ and R₄, when they are not linked together, represent,independently of each other, a hydrogen atom, a C₁₋₄ alkyl group or ahydroxyl group, and/or the compounds for which R₈ represents a hydrogen.

Among these, the compounds for which R₄ represent a hydrogen areparticularly preferred and in particular those for which R₅ represents ahydrogen.

Moreover, the compounds for which R₆ represents an aromatic group otherthan a benzyl, more especially an indanyl, are also preferred and inparticular those containing the abovementioned preferred groups. Amongthe latter, R₁ and R₂ preferably form a C₃₋₆ alkylene group, moreespecially a C₄ alkylene group.

The compounds of formula (I) may be prepared according to the processrepresented in scheme 1.

According to this process, the compounds of formula (I), in which Yrepresents an oxygen and R₇ represents a C₁₋₄ alkyl group, are preparedby reacting a compound of general formula (II)

in which R₁, R₂, R₃, R₄, X, l, m and n are defined as in formula (I),with a compound of general formula (III)

in which R₇ represents a C₁₋₄ alkyl group, R₅ and R₆ are defined as informula (I) and R₉ represents a halogen atom, such as for example achlorine or a bromine, or a hydroxyl group, in an aprotic solvent suchas dichloromethane, in the presence of triethylamine and/or an acidfunction activating agent such as isobutyl chloroformate orcarbonyldiimidazole.

The compounds of the invention of formula (I), for which Y is a sulphuratom and R₇ represents a C₁₋₄ alkyl group, may be obtained by reactingthe compounds (I), previously obtained, with a thiation agent such asLawesson's reagent.

The compounds of the invention of formula (I), for which R₇ is ahydrogen atom, may be obtained by hydrolysing the compounds (I), inwhich R₇ represents a C₁₋₄ alkyl group, according to methods known topersons skilled in the art, for example sodium hydroxide or hydrochloricacid method.

The compounds of formula (II) may be prepared according to processeswell known to persons skilled in the art, or by methods described in theliterature, such as, for example in Boll. Chim. Farm., 121 (1), 16-26(1982), in J. Med. Chem., 33, 62-69 (1990) or in J. Heterocyl. Chem.,30, 1357-59 (1993).

The compounds of formula (III) may be prepared according to processesdescribed in the literature, such as for example in J. Am. Chem. Soc.,90, 3495-3502 (1968) or in J. Med. Chem., 36, 2788-2797 (1993).

The following examples illustrate the invention without however limitingthe scope of the claims. Analyses confirm the structure of thecompounds.

EXAMPLE 1

[R-(R*,S*)]-α-(2,3-Dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicacid.

1.1.-1-Ethyl and 4-(1,1-dimethylethyl)[R-(R*,S*)]-2-(2,3-dihydro-1H-inden-1-yl)butanedioate.

141.5 ml (0.353 mol) of a 2.5 M solution of n-butyllithium in hexane areadded at −70° C. to a solution of 49.5 ml (0.353 mol) ofdiisopropylamine in 400 ml of dry tetrahydrofuran; after 30 min, asolution of 60 g (0.294 mol) of ethyl(S)-2,3-dihydro-1H-indene-1-acetate (obtained according to the methoddescribed in application WO97/06155) in 200 ml of dry tetrahydrofuran isadded; the mixture is stirred at −5° for 2.5 h, it is cooled to −70° C.and then 60.8 ml (0.411 mol) of tert-butyl bromoacetate are added andthe mixture is stirred at room temperature for 16 h; 400 ml of asaturated ammonium chloride solution are added at 0° C., the mixture isstirred for 15 min and then extracted with twice 200 ml of ethylacetate; the combined organic phases are washed with brine, dried oversodium sulphate and evaporated to dryness. After purification bydistillation under vacuum (155-160° C. at 0.2 mmHg), 76.4 g of 1-ethyland 4-(1,1-dimethylethyl)[R-(R*,S*)]-2-(2,3-dihydro-1H-inden-1-yl)butanedioate are obtained inthe form of a yellowish oil; (R*,S*) diastereoisomeric ratio={fraction(1/9)}. Yield 82%. A solution of 54.3 g (0.17 mol) of the precedingproduct in 450 ml of tetrahydrofuran is cooled to −70° C.; 420 ml (0.42mol) of a 1 M solution of sodium salt of1,1,1,3,3,3-hexamethyldisilazane in tetrahydrofuran are added. Themixture is stirred at room temperature for 16 h, cooled to −70° C., 500ml of saturated ammonium chloride solution are added, the mixturestirred for 15 min and then extracted with twice 150 ml of ethylacetate; the combined organic phases are washed with brine, dried withsodium sulphate and evaporated to dryness. After purification bydistillation under vacuum (145-155° C. at 0.2 mmHg), 39 g of 1-ethyl and4-(1,1-dimethylethyl)[R-(R*,S*)]-2-(2,3-dihydro-1H-inden-1-yl)butanedioate are obtained inthe form of a yellowish oil; (R*,S*) diastereoisomeric ratio=6/4. Yield72%.

1.2.-1-Ethyl [R-(R*,S*)]-2-(2,3-dihydro-1H-inden-1-yl)butanedioate.

111 ml (1.44 mol) of trifluoroacetic acid are added at 0° C. to asolution of 39 g (0.122 mol) of 1-ethyl and 4-(1,1-dimethylethyl)[R-(R*,S*)]-2-(2,3-dihydro-1H-inden-1-yl)butanedioate in 600 ml ofdichloromethane; the mixture is stirred at room temperature for 16 h andthen evaporated to dryness; 32.47 g of 1-ethyl[R-(R*,S*)]-2-(2,3-dihydro-1H-inden-1-yl)butanedioate are obtained inthe form of a reddish oil. The (R*,S*) diastereoisomeric ratio=6/4.Quantitative yield.

1.3.-Ethyl[R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoate.

13 g (0.08 mol) of carbonyldiimidazole are added at 0° C. to a solutionof 23.4 g (0.0735 mol) of 1-ethyl[R-(R*,S*)]-2-(2,3-dihydro-1H-inden-1-yl)butanedioate in 280 ml ofdichloromethane; the mixture is stirred at room temperature for 1 h andthen a solution of 14.2 g (0.08 mol) of 8-azaspiro[4.5]decane and 10.2 g(0.1 mol) of triethylamine in 340 ml of dichloromethane is added. Themixture is stirred for 16 h at room temperature, poured over 400 ml ofcold water, the mixture is stirred for 15 min and then extracted withthree times 150 ml of ethyl acetate; the combined organic phases arewashed successively with 150 ml of saturated sodium hydrogen carbonatesolution, with 150 ml of a 5% aqueous citric acid solution and then withbrine, dried with sodium sulphate and evaporated to dryness. Afterpurifying on a silica column with the aid of the {fraction (1/9)} ethylacetate/hexane eluent mixture, 24.57 g of ethyl[R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoateare obtained in the form of a slightly yellow oil; (R*,S*)diastereoisomeric ratio=6/4. Yield 87%.

1.4-[R-(R*,S*)]-α-(2,3-Dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicacid.

A solution of 6.8 g (0.17 mol) of sodium hydroxide in 60 ml of water isadded to a solution of 20 g (0.0522 mol) of ethyl[R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoatein a mixture of 150 ml of tetrahydrofuran and 150 ml of methanol, andthe mixture is stirred for 3 h at 60° C. The mixture is concentrated,200 ml of water are added, the solution obtained is washed with twice150 ml of diethyl ether and then acidified at 0° C. with 6 Mhydrochloric acid to pH 2 and it is extracted with twice 250 ml ofdichloromethane; the organic phases are washed with brine, dried withsodium sulphate and evaporated to dryness. 16 g of[R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicacid are obtained in the form of a colourless oil; the (R*,S*)diastereoisomeric ratio=6/4. Yield 86%; 14 g (0.0295 mol) of this acidare dissolved in 320 ml of ethyl acetate, the solution is cooled to 0°C. and then a solution of 3.57 g (0.0295 mol) of (R)(+)-α-methylbenzylamine in 25 ml of ethyl acetate is added; the mixtureis stirred at room temperature for 16 h, the precipitate formed isfiltered, it is stirred in 30 ml of ethyl acetate, it is filtered andthen it is dried; 7 g of a white solid of melting point 155-156° C. areobtained; 75 ml of water are added to a suspension of 7 g of thepreceding solid, the solution is cooled to 0° C. and acidified with 6 Mhydrochloric acid to pH 2; the mixture is stirred for 15 min with 170 mlof diisopropyl ether, the organic phase is decanted off and the aqueousphase is extracted with 170 ml of diisopropyl ether; the organic phasesare washed with brine, dried over sodium sulphate and then evaporated todryness. 4.9 g of[R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicacid are obtained in the form of a white solid; (R*,S*) diastereomericratio >99%. The product melts at 137° C. with decomposition.[α]_(D)=−26° (c=5%, ethanol)

EXAMPLE 2

Calcium[R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoate

3 ml (0.04 mol) of a 25% ammonium hydroxide solution are added to asuspension of 4.5 g (0.0126 mol) of[R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicacid in 225 ml of water, the mixture is stirred for 20 min and then asolution of 1 g (0.009 mol) of calcium chloride in 25 ml of water isadded dropwise; the mixture is stirred for 1.5 h, the precipitate formedis filtered, it is washed with cold water and then it is dried undervacuum. 4.2 g of calcium[R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoateare obtained in the form of a white solid; (R*,S*) diastereomericratio >99%. Yield 89%. Melting point 231-233° C. [α]_(D)=−8° (c=2.5%,dimethyl sulphoxide)

EXAMPLE 3

[S-(S*,S*)]-α-(2,3-Dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicAcid

This compound was prepared according to the process described in Example1, using (S)(−)-α-methylbenzylamine as resolving reagent. The[S-(S*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]-decane-8-butanoicacid exists as a white solid which melts at 144-146° C. withdecomposition. [α]_(D)=+22° (c=5%, ethanol).

EXAMPLE 4

[R-(R*,R*)]-α-(2,3-Dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicAcid

This compound was prepared according to the process described in Example1, using ethyl (R)-2,3-dihydro-1H-indene-1-acetate as starting material.The[R-(R*,R*)]-α-(2,3-Dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicacid exists as a white solid which melts at 139-141° C. [α]_(D)=−19.2°(c=5%, ethanol).

EXAMPLE 5

[S-(S*,R*)]-α-(2,3-Dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicAcid.

This compound was prepared according to the process of Example 4, using(S)(−)-α-methylbenzylamine as resolving reagent. The[S-(S*,R*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicacid exists as a white solid which melts at 78-84° C. [α]_(D)=+28°(c=5%, ethanol).

EXAMPLE 6

1,4-Dithia-8-azaspiro[4.5]decane Hydrochloride.

6.1.-8-(Phenylmethyl)-1,4-dithia-8-azaspiro[4.5]-decane.

31.5 g (0.165 mol) of p-toluenesulphonic acid monohydrate and 16.9 g(0.18 mol) of ethanedithiol are added to a solution of 28.35 g (0.150mol) of 1-benzyl-4-piperidinone in 600 ml of toluene; the mixture isheated under reflux in a Dean-Stark system for 6 h, the solvent isevaporated off, 500 ml of ethyl acetate are added, the solution iswashed successively with twice 100 ml of saturated sodium carbonatesolution, with water and with brine; it is dried with sodium sulphateand then evaporated to dryness. The residue is purified bychromatography on silica gel with the aid of the 3/97 ethylacetate/hexane eluent mixture. 17.1 g of8-(phenylmethyl)-1,4-dithia-8-azaspiro[4.5]decane are obtained in theform of a white solid. Yield 42%. Melting point 51-53° C.

6.2.-1,4-Dithia-8-azaspiro[4.5]decane Hydrochloride.

0.74 ml (0.007 mol) of 1-chloroethyl chloroformate is added to asolution of 1.6 g (0.006 mol) of8-(phenylmethyl)-1,4-dithia-8-azaspiro-[4.5]decane in 20 ml ofdichloroethane; the mixture is heated under reflux for 1.5 h, it iscooled to room temperature, 8 ml of 1 M sodium hydroxide are added, theorganic phase is decanted off, the aqueous phase is washed with 25 ml ofdichloromethane, the organic phases are dried with sodium sulphate andthen evaporated to dryness; the residue is dissolved in 35 ml ofmethanol and the solution is heated at 60° C. for 40 min; the solvent isevaporated off and the solid obtained is triturated with diisopropylether; 0.993 g of 1,4-dithia-8-azaspiro[4.5]decane hydrochloride is thusobtained in the form of a white solid. Yield 78%. Melting point >250° C.

The compounds of the invention are assembled in the following table withtheir physical characteristics without, however, limiting the scope ofthe protection. It was possible for them to be prepared according to theprocesses described.

TABLE

[α]_(D)° m.p. c = 5%, No. X R₁ R₂ R₃ R₄ R₅ R₆ l m n Y R₇ (° C.) ConfigEthanol  1 C —(CH₂)₄— H H H

1 1 2 O H 125-129 (R*,R*) —  2 C —(CH₂)₄— H H H

1 1 2 O H 120-124 (R*,S*) —  3 C —(CH₂)₄— H H H

1 1 2 O C₂H₅ 90-92 (R*,S*) —  4 C —(CH₂)₄— H H H

1 1 2 O (Ca⁺⁺)_(½) 231-233 d [R(R*,S*)] −8* (c = 2.5%)  5 C —(CH₂)₄— H HH

1 1 2 O H 137 d [R(R*,S*)] −26  6 C —(CH₂)₄— H H H

1 1 2 S (Ca⁺⁺)_(½) 230-232 d [R(R*,S*)] —  7 C —(CH₂)₄— H H H

1 1 2 O H 144-146 d [S(S*,S*)] +22  8 C —(CH₂)₄— H H H

1 1 2 O H 136-142 [R(R*,S*)] —  9 C —(CH₂)₄— H H H

1 1 2 O H 90 d [R(R*,S*)] — 10 C —(CH₂)₄— H H H

1 1 2 O H 87 d [R(R*,S*)] — 11 C —(CH₂)₄— H H H

1 1 2 O H 116 d [R(R*,S*)] — 12 C —(CH₂)₄— H H H

1 1 2 O H 139-141 [R(R*,R*)] −19.2 13 C —(CH₂)₄— H H H

1 1 2 O H 78-84 [S(S*,R*)] +28 14 C CH₃ CH₃ H H H

1 1 2 O H 154-160 (R*,R*) — 15 C CH₃ CH₃ H H H

1 1 2 O H 120-125 (R*,S*) — 16 C CH₃ CH₃ H H H

1 1 2 O H 173-175 [S(S*,S*)] +17.6 (c = 2.5%) 17 C CH₃ CH₃ H H H

1 1 2 O H 113-115 [R(R*,S*)] — 18 C CH₃ H H H H

1 1 2 O H 145-148 (R*,R*) — 19 C CH₃ H H H H

1 1 2 O (Ca⁺⁺)_(½) 177-191 (R*,S*) — 20 C CH₃ H H H H

1 1 2 O H 194-196 [S(S*,S*)] +28* 21 C CH₃ H H H H

1 1 2 O (Ca⁺⁺)_(½) 234-238 [R(R*,S*)] — 22 C Ph— CH₂ H H H H

1 1 2 O H 146 (R*,S*) — 23 C

H H H H

1 1 2 O H 170-200 (R*,S*) — 24 C

H H H H

1 1 2 O H 143-145 (R*,S*) — 25 C H H H H H

1 1 2 O Na⁺ 195-197 (R*,S*) — 26 C CO— NH₂ H H H H

1 1 2 O H 159-165 (R*,R*) — 27 C

H H H H

1 1 2 O H 133-137 (R*,R*) — 28 C

H H H H

1 1 2 O (Ca⁺⁺)_(½) 208 (R*,S*) — 29 C

H H H H

1 1 2 O H 121-122 [R(R*,S*)] — 30 C

H H H H

1 1 2 O H 139-144 [S(S*,S*)] — 31 O — — H H H

0 0 2 O Na⁺ 205-210 (R*,S*) — 32 S — — H H H

0 0 2 O H 148 (R*,S*) — 33 SO₂ — — H H H

0 0 2 O Na⁺ >250 (R*,S*) — 34 N CH₃ — H H H

1 0 2 O H 100-120 (R*,S*) — 35 C H

H H

1 1 1 O H 158-160 (R*,R*) — 36 C H

H H

1 1 1 O (Ca⁺⁺)_(½) >250 (R*,S*) — 37 C H

H H

1 1 1 O H 184-186 (R*,R*) — 38 C H

H H

1 1 1 O H 102-108 (R*,S*) — 39 C H H H H H

1 1 1 O Na⁺ 232-236 (R*,S*) — 40 C H — — H H

1 1 1 O H 135-138 (R*,S*) — 41 C H OH OH H H

1 1 1 O Na⁺ >250 (R*,S*) — 42 C —(CH₂)₅— H H H

1 1 2 O H 132-134 (R*,S*) — 43 C —(CH₂)₅— H H H

1 1 1 O H 110-113 (R*,S*) — 44 C —(CH₂)₄— H H H

1 1 1 O H 142-144 (R*,R*) — 45 C —O(CH₂)₂O— H H H

1 1 2 O H 156-158 (R*,R*) — 46 C —O(CH₂)₂O— H H H

1 1 2 O Na⁺ >250 (R*,S*) — 47 C —O(CH₂)₂O— H H H

1 1 2 O H 200-206 [S(S*,S*)] +26.4* 48 C —O(CH₂)₂O— H H H

1 1 2 O Na⁺ >250 [R(R*,S*)] — 49 C —S(CH₂)₂S— H H H

1 1 2 O H 121 (R*,S*) — 50 C —S(CH₂)₂S— H H H

1 1 2 O H 200-202 [S(S*,S*)] — 51 C —S(CH₂)₂S— H H H

1 1 2 O H 120-123 [R(R*,S*)] −41.6* 52 C —SO₂(CH₂)₂SO₂ _(⁻) H H H

1 1 2 O H 215-220 [R(R*,S*)] — 53 C

H H H

1 1 2 O H 102 d [R(R*,S*)] — 54 C —(CH₂)₄— H H OH

1 1 2 O H 90 −14.4 (c = 2.5%) 55 C H

H H

1 1 1 O Na⁺ 211 d (R*,S*) — 56 C H

H H

1 1 1 O H 171-174 d (R*,S*) — 57 C —(CH₂)₄— H H

H 1 1 2 O H 124 d [R(R*,S*)] −74.4 58 C H

H H

1 1 1 O Na⁺ 193-198 (S) +1.6 (c = 2.5%) 59 C H

H H

1 1 1 O H 142-145 (S) −18* 60 C H

H H

1 1 1 O H 107 (R,S) — 61 C H

H H

1 1 1 O H 150 d (R*,S*) — 62 C —(CH₂)₄— H H H

1 1 2 O H 139-142 (R*,R*) — 63 C —(CH₂)₄— H H H

1 1 2 O H 139-142 (R*,S*) — 64 C H

H H

1 1 1 O H 56-58 (R*,S*) — 65 C H

H H

1 1 1 O H 155-157 (R*,S*) — 66 C —(CH₂)₄— H H H

1 1 2 O H 144-146 (R*,S*) — 67 C —(CH₂)₄— H H H

1 1 2 O H 171-173 (R*,S*) — In this table: d = decomposition

Ph represents a phenyl *performed in dimethyl sulphoxide

The compounds of the invention were tested in various biological trials.

They were in particular subjected to a test for hypoglycaemic activityin rats. This trial was carried out on rats that had been kept fastingfor 20 h. The test products are administered by the oral route; bloodsamples are collected from the tail 0.5, 1, 2, 3, 5 and 7 h afteradministration of the product, according to the method described by H.Ohnota in The Journal of Pharmacology and Experimental Therapeutics,269, No. 2, 489-495 (1994).

The compounds of the invention reduce by 30 to 40% the basal glycaemiaat doses of between 0.1 and 10 mg/kg.

They were also subjected to a test for antihyperglycaemic activity inrats according to the method described by R. S. Ho et al., in Arch. Int.Pharmacodyn. 237, 98 (1979).

This trial is carried out on mice that had been kept fasting for 20 h.The test products are administered by the oral route 30 min before theadministration of a glucose overload (1.5 g/kg). The animals aresacrificed by decapitation 30 min after the glucose overload and theirglycaemia is determined as above.

The median effective doses (ED₅₀) of the compounds of the invention arebetween 0.1 and 10 mg/kg. In this trial, the reference compound KAD1229has a median effective dose of 1.5 mg/kg.

The in vivo activity of the compounds of the present invention wasstudied in an experimental model of plantar inflammation in rats.

Inflammatory oedema of the paw of rats induced by the intradermalinjection of carrageenan (CAR) (1k, v/v) is obtained and evaluatedaccording to the method of Winter C. A., and Risley E. A.(Carrageenan-induced edema in the hindpaw of rats as an assay foranti-inflammatory drugs. Proc. Soc. Axp. Biol. Med, 19632, 11, 544-547).

The compounds of the invention are given orally 1 hour before theinjection of CAR. A 1% solution of CAR in a saline solution is injectedby the s.c. route into the sub-plantar part of the right hindpaw ofrats.

The volume resulting from the inflammatory reaction is measured byplethysmography after 1.5, 3 and 4.5 hours from the injection of CAR.

The compounds of the invention at doses of is between 0.5 and 10 mg/kgby the oral route confer lasting inhibition of the inflammation induced(between 1.5, 3 and 4.5 hours after the injection of CAR) of between 20and 90% relative to the control.

The results show that the compounds of the invention exhibit “in vivo”hypo- and antihyperglycaemic, and anti-inflammatory properties. They cantherefore be used in the treatment of hyperglycaemia, diabetes, obesityand inflammation. In the case of inflammation, they can be used moreparticularly in neuropathies in diabetics, polyarthritis,osteoarthritis, lumbago, traumatological pain, inflammation in the ENTdomain.

The compounds of the invention may be provided, in combination with anyappropriate excipient, in any form suitable for administration by theoral or parenteral route, for example in the form of tablets, gelatincapsules, sugar-coated tablets or oral or injectable solutions.

The compounds of the invention may be administered in daily doses ofbetween about 1 and 100 mg in adults by the oral route, or between about0.1 and 100 mg by the parenteral route.

What is claimed is:
 1. A compound of general formula (I)

in which: R₁ represents a hydrogen atom, hydroxyl, a C₁₋₄ alkyl C₁₋₄hydroxyalkyl, C₄₋₇ cycloalkyl or C₁₋₄ alkyloxy(C₁₋₄ alkyl) group, anaminocarbonyl group, a benzyl, a heterocycloalkyl or heteroaryl groupcomprising from 4 to 5 carbon atoms and a heteroatom selected from thegroup consisting of nitrogen, sulphur and oxygen, the heterocycloalkylor heteroaryl group being optionally substituted with one or twosubstituents selected from the group consisting of a hydroxyl, a C₁₋₄alkyl group and a halogen; R₂, R₃ and R₄, which may be identical ordifferent, represent independently of each other a hydrogen atom, a C₁₋₄alkyl group, a C₄₋₇ cycloalkyl group, a hydroxyl group, an aminocarbonylgroup or a heteroaryl group comprising from 4 to 5 carbon atoms and aheteroatom selected from the group consisting of nitrogen, sulphur andoxygen, the heteroaryl group being optionally substituted with one ortwo substituents selected from the group consisting of a hydroxyl group,a C₁₋₄ alkyl group and a halogen; or R₁ and R₂ together form a C₃₋₆alkylene group, a C₂₋₃ alkylenedioxy group, a C₂₋₃ alkylenedithio group,—(O₂)S—C₂₋₃ alkylene-S(O₂)— or a group —CH₂NHC(O)CH₂—; or R₂ and R₃together form a propylene or butylene group, a C₁₋₃ alkylenedioxy group,a carbonyldioxy group or a 2-butenylene; or R₂ and R₃ together form withthe atoms carrying them a norbornane or a 5-norbornene or a bond inorder to give a double bond between the atoms carrying them, X being acarbon atom; R₅ represents a hydrogen atom, a hydroxyl group or, when R₆represents a hydrogen, a 1-indanyl group; R₆ represents an aromaticgroup chosen from the following groups:

or, when R₂ and R₃ together form a C₁₋₃ alkylenedioxy or carbonyldioxygroup, a benzyl optionally substituted with one or two substituentsselected from the group consisting of a halogen and a C₁₋₄ alkyl group,or R₆ represents a hydrogen, when R₅ represents a 1-indanyl group; R₇represents a hydrogen atom or a C₁₋₄ alkyl group; R₈ represents ahydrogen, an acetyl, a benzoyl, a C₁₋₄ alkyl group, optionallysubstituted with a hydroxyl; or a C₁₋₂ alkylphenyl group, optionallysubstituted on the alkyl group with a hydroxyl, X represents a carbon,nitrogen, oxygen or sulphur atom or a sulphonyl group, Y represents anoxygen or sulphur atom, n is equal to 1 or 2; l is equal to 1 and m isequal to 0 when X represents a nitrogen atom; l and m are equal to 0when X represents a sulphur or oxygen atom or a sulphonyl; they areequal to 1 when X represents a carbon atom, and optionally in the formof an enanitiomer, a diastereoisomer or a mixture of these variousforms, or the addition salts with pharmaceutically acceptable bases oracids of one of these forms.
 2. A compound according to claim 1 whereinn is equal to 2 and R₇ is a hydrogen atom.
 3. A compound according toclaim 1 wherein it is in the form of a sodium or calcium salt, such thatR₇ represents a sodium or calcium atom. 4.[R-(R*,S*)]-α-(2,3-Dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicacid according to claim
 1. 5.[S-(S*,R*)]-α-(2,3-Dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicacid according to claim
 1. 6.[R-(R*,R*)]-α-(2,3-Dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicaccording to claim
 1. 7.[S-(S*,S*)]-α-(2,3-Dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoicacid according to claim
 1. 8. A process for the preparation of acompound of formula (I), according to claim 1 wherein a compound offormula (II)

in which R₁, R₂, R₃, R₄, X, l, m and n are defined as in formula (I), isreacted with a compound of general formula (III)

in which R₇ represents a C₁₋₄ alkyl group, R₅ and R₆ are defined as informula (I) and R₉ represents a halogen atom or a hydroxyl group,optionally in the presence of an activating agent, to give the compoundsof formula (I) in which R₁, R₂, R₃, R₄, R₅, R₆, R₇, X, l, m and n are asdefined above, optionally followed by a thiation reaction to give thecompounds of formula (I) in which Y is a sulphur atom, and by hydrolysisto give the compounds of formula (I), in which R₇ is a hydrogen atom. 9.A method for the treatment of hyperglycaemia, diabetes, obesity orinflammation which comprises administering to a patient in need of suchtreatment an effective amount of a compound according to claim
 1. 10. Apharmaceutical composition which comprises at least one compoundaccording to claim 1 together with one or more appropriate excipients.11. A compound according to claim 1 wherein R₂, R₃ and R₄ represent,independently of each other, a hydrogen atom, a C₁₋₄ alkyl group or ahydroxyl group.
 12. A compound according to claim 11 wherein R₄represents a hydrogen and R₅ represents a hydrogen.
 13. A compoundaccording to one of claim 1 wherein R₆ represents an aromatic groupother than a benzyl.
 14. A compound according to claim 13 wherein R₆represents an indanyl.
 15. A compound according to claim 14 wherein R₁and R₂ together form a C₃₋₆ alkylene group.
 16. A method for thetreatment of hyperglycaemia, diabetes, obesity or inflammation whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 2. 17. A method forthe treatment of hyperglycaemia, diabetes, obesity or inflammation whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 3. 18. A method forthe treatment of hyperglycaemia, diabetes, obesity or inflammation whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 4. 19. A method forthe treatment of hyperglycaemia, diabetes, obesity or inflammation whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 5. 20. A method forthe treatment of hyperglycaemia, diabetes, obesity or inflammation whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 6. 21. A method forthe treatment of hyperglycaemia, diabetes, obesity or inflammation whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 7. 22. A method forthe treatment of hyperglycaemia, diabetes, obesity or inflammation whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 11. 23. A method forthe treatment of hyperglycaemia, diabetes, obesity or inflammation whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 12. 24. A method forthe treatment of hyperglycaemia, diabetes, obesity or inflammation whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 13. 25. A method forthe treatment of hyperglycaemia, diabetes, obesity or inflammation whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 14. 26. A method forthe treatment of hyperglycaemia, diabetes, obesity or inflammation whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 15. 27. Apharmaceutical composition which comprises at least one compoundaccording to claim 2 together with one or more appropriate excipients.28. A pharmaceutical composition which comprises at least one compoundaccording to claim 3 together with one or more appropriate excipients.29. A pharmaceutical composition which comprises at least one compoundaccording to claim 4 together with one or more appropriate excipients.30. A pharmaceutical composition which comprises at least one compoundaccording to claim 5 together with one or more appropriate excipients.31. A pharmaceutical composition which comprises at least one compoundaccording to claim 6 together with one or more appropriate excipients.32. A pharmaceutical composition which comprises at least one compoundaccording to claim 7 together with one or more appropriate excipients.33. A pharmaceutical composition which comprises at least one compoundaccording to claim 11 together with one or more appropriate excipients.34. A pharmaceutical composition which comprises at least one compoundaccording to claim 12 together with one or more appropriate excipients.35. A pharmaceutical composition which comprises at least one compoundaccording to claim 13 together with one or more appropriate excipients.36. A pharmaceutical composition which comprises at least one compoundaccording to claim 14 together with one or more appropriate excipients.37. A pharmaceutical composition which comprises at least one compoundaccording to claim 15 together with one or more appropriate excipients.